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Relative Binding Energies Predict Crystallographic Binding Modes of Ethionamide Booster Lead Compounds
Univ Durham, Dept Chem, South Rd, Durham DH1 3LE, England.
Univ Oxford, Chem Res Lab, Dept Chem, Mansfield Rd, Oxford OX1 3TA, England.ORCID iD: 0000-0002-6062-8209
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.ORCID iD: 0000-0002-3190-1173
Univ Durham, Dept Chem, South Rd, Durham DH1 3LE, England;Univ Durham, Dept Biosci, Durham DH1 3LE, England;Univ Durham, Biophys Sci Inst, Durham DH1 3LE, England.ORCID iD: 0000-0002-9949-4471
2019 (English)In: Journal of Physical Chemistry Letters, ISSN 1948-7185, E-ISSN 1948-7185, Vol. 10, no 9, p. 2244-2249Article in journal (Refereed) Published
Abstract [en]

Transcriptional repressor EthR from Mycobacterium tuberculosis is a valuable target for antibiotic booster drugs. We previously reported a virtual screening campaign to identify EthR inhibitors for development. Two ligand binding orientations were often proposed, though only the top scoring pose was utilized for filtering of the large data set. We obtained biophysically validated hits, some of which yielded complex crystal structures. In some cases, the crystallized binding mode and top scoring mode agree, while for others an alternate ligand binding orientation was found. In this contribution, we combine rigid docking, molecular dynamics simulations, and the linear interaction energy method to calculate binding free energies and derive relative binding energies for a number of EthR inhibitors in both modes. This strategy allowed us to correctly predict the most favorable orientation. Therefore, this widely applicable approach will be suitable to triage multiple binding modes within EthR and other potential drug targets with similar characteristics.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2019. Vol. 10, no 9, p. 2244-2249
National Category
Structural Biology
Identifiers
URN: urn:nbn:se:uu:diva-383836DOI: 10.1021/acs.jpclett.9b00741ISI: 000466991300033PubMedID: 30965004OAI: oai:DiVA.org:uu-383836DiVA, id: diva2:1318805
Funder
The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)Available from: 2019-05-28 Created: 2019-05-28 Last updated: 2019-05-28Bibliographically approved

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